RT info:eu-repo/semantics/article
T1 Inhibition of polyamine biosynthesis reverses Ca2+ channel remodeling in colon cancer cells
A1 González Gutiérrez, Lucía
A1 Hernández Morales, Miriam
A1 Núñez Llorente, Lucía
A1 Villalobos Jorge, Carlos
K1 Colorectal cancer
K1 Cáncer colorrectal
K1 Difluoromethylornithine
K1 Difluorometilornitina
K1 Polyamines
K1 Poliaminas
AB Store-operated Ca2+ entry (SOCE) is the most important Ca2+ entry pathway in non-excitable cells. Colorectal cancer (CRC) shows decreased Ca2+ store content and enhanced SOCE that correlate with cancer hallmarks and are associated to remodeling of store-operated channels (SOCs). Normal colonic cells display small, Ca2+-selective currents driven by Orai1 channels. In contrast, CRC cells display larger, non-selective currents driven by Orai1 and transient receptor potential canonical type 1 channels (TRPC1). Difluoromethylornithine (DFMO), a suicide inhibitor of ornithine decarboxylase (ODC), the limiting step in polyamine biosynthesis, strongly prevents CRC, particularly when combined with sulindac. We asked whether DFMO may reverse SOC remodeling in CRC. We found that CRC cells overexpress ODC and treatment with DFMO decreases cancer hallmarks including enhanced cell proliferation and apoptosis resistance. Consistently, DFMO enhances Ca2+ store content and decreases SOCE in CRC cells. Moreover, DFMO abolish selectively the TRPC1-dependent component of SOCs characteristic of CRC cells and this effect is reversed by the polyamine putrescine. Combination of DFMO and sulindac inhibit both SOC components and abolish SOCE in CRC cells. Finally, DFMO treatment inhibits expression of TRPC1 and stromal interaction protein 1 (STIM1) in CRC cells. These results suggest that polyamines contribute to Ca2+ channel remodeling in CRC, and DFMO may prevent CRC by reversing channel remodeling.
PB MDPI
SN 2072-6694
YR 2019
FD 2019
LK http://uvadoc.uva.es/handle/10324/45023
UL http://uvadoc.uva.es/handle/10324/45023
LA eng
NO Cancers, 2019, vol. 11, n. 1. 17 p.
NO Producción Científica
DS UVaDOC
RD 17-jul-2024